Various reports have identified the role of two isomers of 8,14-dihydroxy-7,8-dihydrocodeinone in the formation of 14-hydroxycodeinone—an α,β-unsaturated ketone (“ABUK”) and a purportedly genotoxic impurity in oxycodone hydrochloride. For example, U.S. Pat. No. 7,683,072 of Chapman et al. notes that “[d]uring salt formation reactions known in the art, the 8,14-dihydroxy-7,8-dihydrocodeinone component is converted to 14-hydroxycodeinone by acid-catalyzed dehydration. See also Weiss, J. Org. Chem., 22(11): 1505-08 (1957). Thus, 14-hydroxycodeinone is increased in the final product.” (col. 8, lines 7-12). Similarly, Cox (WO 2008/070656 and WO 2008/070658) notes that “DHDHC [8,14-dihydroxy-7,8-dihydrocodeinone] is easily converted to 14-hydroxycodeinone. This conversion occurs during the conversion of oxycodone base (a.k.a. oxycodone free base) to oxycodone hydrochloride, thus 14-hydroxycodeinone is present in the final oxycodone hydrochloride.” (p. 3, lines 5-7). Thus, the isomeric 8,14-dihydroxy-7,8-dihydrocodeinone diols are understood to be unstable such that, during conversion of the oxycodone free base to oxycodone hydrochloride, they undergo acid-catalyzed dehydration to form the 14-hydroxycodeinone ABUK impurity. Weiss teaches that 8,14-dihydroxy-7,8-dihydrocodeinone can be recrystallized from hot 2N HCl if the treatment is rapid, but also reports that treatment in “dilute acid (1:1) in a boiling water bath for 20 minutes” converts the dihydroxy species to 14-hydroxycodeinone. While Weiss does not indicate the mixture of dihydroxy isomers handled during the 2N recrystallization and subsequent hydrolysis to 14-hydroxycodeinone, it implies that both isomers of 8,14-dihydroxy-7,8-dihydrocodeinone will dehydrate to form 14-hydroxycodeinone. Recent reports, including the Chapman '072 patent, and Baldwin (see Baldwin Declaration in support of U.S. patent application Ser. No. 11/729,741) have pointed to the alpha isomer as the apparent more hydrolytically unstable diol of 8,14-dihydroxy-7,8-dihydrocodeinone. Baldwin cites Example 3 of Chapman's U.S. Pat. No. 7,674,800 as demonstrating that dehydration occurs under conditions of aqueous HCl as low as 0.2N at 75° C. Baldwin contrasts this with the Weiss report to assert that one of the two isomers is much more prone to acid catalyzed dehydration.
The present inventors prepared and characterized the 8β,14-dihydroxy-7,8-dihydrocodeinone and used this to develop analytical methodology to measure the alpha and beta isomers by LC/MS to a detection limit of 2 ppm. Two HPLC peaks at relative retention times (RRT) 0.82 and 0.91 versus oxycodone were observed as having a mass corresponding to 8,14-dihydroxy-7,8-dihydrocodeinone upon LC/MS analysis. The peak at RRT 0.91 was identified as the 813 diol. Exposure of a mixture of the two species to acid showed a correlation between the loss of the RRT 0.82 peak with the growth of 14-hydroxycodeinone over a 20 hour period. The peak at RRT 0.91 degraded little under the same conditions over the 20 hour period. On the basis of this study and in view of Baldwin's assertions, the peak at RRT 0.82 was assigned as the 8α diol for the purposes of developing the invention.
A variety of approaches to producing oxycodone hydrochloride with low levels of 14-hydroxycodeinone have been published. The Chapman '072 patent, as well as other patents in the Chapman patent family, and U.S. Patent Application Publication No. 2007/0149559 to Shafer et al., for example, report methods wherein the diols, as contaminants in oxycodone, are dehydrated using aqueous acid or organic acids in organic solvents to form 14-hydroxycodeinone. Chapman describes converting the 14-hydroxycodeinone to oxycodone by hydrogenation as the dehydration occurs. This prevents reversal by rehydration of the 7,8 double bond and minimizes the possibility of having 8,14-dihydroxy-7,8-dihydrocodeinone as an ABUK precursor in the final oxycodone hydrochloride product. Shafer traps the 14-hydroxycodeinone with a thiol nucleophile, forming a water-extractable adduct that can be readily separated from oxycodone.
International Patent Application Publication No. WO 2007/103105 of Buehler et al. likewise describes conditions that may dehydrate the diols to an extent and, in a fashion similar to Shafer, treats the 14-hydroxycodeinone with a sulfur nucleophile or a sulfur-containing inorganic acid or salt thereof to form a water-soluble adduct. The Buehler procedure uses species akin to meta-bisulfite, which react with oxycodone in a 1,2 fashion and with 14-hydroxycodeinone in a 1,4 and 1,2 fashion to form soluble adducts of each. Upon a pH adjustment to ca. pH 9, the 1,2 sulfite adducts hydrolyze to the ketone; however, the 1,4 adduct derived from 14-hydroxycodeinone remains intact and confers water solubility. At pH 9, the oxycodone precipitates or may be preferentially extracted into organic solvent and the adducted 14-hydroxycodeinone remains in the aqueous mixture. The Shafer approach differs in emphasizing the formation of the 1,4 adduct of 14-hydroxycodeinone and does not explicitly rely upon selective 1,2 hydrolysis to recover and separate the oxycodone from the water-soluble 1,4 adduct.
The derivatization of 14-hydroxycodeinone with a sulfur-based reagent, either as a free species or resin-bound, is common to Shafer, Cox and Buehler. At least Chapman and Shafer find commonality in: (1) forcing the dehydration of the diols in the presence of oxycodone; and (2) subsequently consuming or removing the resulting 14-hydroxycodeinone either as oxycodone or as a derivative separable from oxycodone.